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WO2000058013A1 - Homogeneisation de petits volumes de melanges de reactions chimiques par centrifugation et chauffage - Google Patents

Homogeneisation de petits volumes de melanges de reactions chimiques par centrifugation et chauffage Download PDF

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Publication number
WO2000058013A1
WO2000058013A1 PCT/SE2000/000586 SE0000586W WO0058013A1 WO 2000058013 A1 WO2000058013 A1 WO 2000058013A1 SE 0000586 W SE0000586 W SE 0000586W WO 0058013 A1 WO0058013 A1 WO 0058013A1
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WO
WIPO (PCT)
Prior art keywords
reaction vessels
reaction
heating
rotor
vessels
Prior art date
Application number
PCT/SE2000/000586
Other languages
English (en)
Inventor
Mats Malmquist
Original Assignee
Alphahelix Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE9901104A external-priority patent/SE9901104D0/xx
Priority claimed from SE9902378A external-priority patent/SE9902378D0/xx
Application filed by Alphahelix Ab filed Critical Alphahelix Ab
Priority to DE60044429T priority Critical patent/DE60044429D1/de
Priority to AT00921255T priority patent/ATE468175T1/de
Priority to AU41591/00A priority patent/AU766869B2/en
Priority to JP2000607757A priority patent/JP4681736B2/ja
Priority to US09/937,383 priority patent/US6783993B1/en
Priority to CA002366732A priority patent/CA2366732C/fr
Priority to HK02105260.0A priority patent/HK1043749B/en
Priority to EP00921255A priority patent/EP1173284B1/fr
Publication of WO2000058013A1 publication Critical patent/WO2000058013A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B01L7/525—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples with physical movement of samples between temperature zones
    • B01L7/5255—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples with physical movement of samples between temperature zones by moving sample containers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F29/00—Mixers with rotating receptacles
    • B01F29/15—Use of centrifuges for mixing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B04—CENTRIFUGAL APPARATUS OR MACHINES FOR CARRYING-OUT PHYSICAL OR CHEMICAL PROCESSES
    • B04B—CENTRIFUGES
    • B04B15/00—Other accessories for centrifuges
    • B04B15/02—Other accessories for centrifuges for cooling, heating, or heat insulating
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B04—CENTRIFUGAL APPARATUS OR MACHINES FOR CARRYING-OUT PHYSICAL OR CHEMICAL PROCESSES
    • B04B—CENTRIFUGES
    • B04B5/00—Other centrifuges
    • B04B5/04—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers
    • B04B5/0407—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers for liquids contained in receptacles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B04—CENTRIFUGAL APPARATUS OR MACHINES FOR CARRYING-OUT PHYSICAL OR CHEMICAL PROCESSES
    • B04B—CENTRIFUGES
    • B04B5/00—Other centrifuges
    • B04B5/04—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers
    • B04B5/0407—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers for liquids contained in receptacles
    • B04B5/0414—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers for liquids contained in receptacles comprising test tubes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B04—CENTRIFUGAL APPARATUS OR MACHINES FOR CARRYING-OUT PHYSICAL OR CHEMICAL PROCESSES
    • B04B—CENTRIFUGES
    • B04B5/00—Other centrifuges
    • B04B5/04—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers
    • B04B5/0407—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers for liquids contained in receptacles
    • B04B5/0414—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers for liquids contained in receptacles comprising test tubes
    • B04B5/0421—Radial chamber apparatus for separating predominantly liquid mixtures, e.g. butyrometers for liquids contained in receptacles comprising test tubes pivotably mounted
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/44—Sample treatment involving radiation, e.g. heat
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00465—Separating and mixing arrangements
    • G01N2035/00495—Centrifuges
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/25375—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]

Definitions

  • the present invention relates to the field of chemical reactions requiring temperation and/or incubation of the reaction mixture and in particular chemical reactions in liquid media.
  • the present invention discloses a new device and method for efficient and homogenous mixing, temperation and/or incubation of reaction mixtures.
  • reaction vessels for example bringing them in contact with an open flame, hot gas, hot liquid, hot sand or a solid material. This procedure is often referred to as incubation.
  • thermocycling processes e.g. for performing polymerase chain reactions, also known as PCR-reactions
  • long temperation periods also leads to unwanted side-reactions, sometimes causing severe quality problems with respect to the accuracy and specificity of the obtained PCR-product.
  • thermocycling devices for processes in which proper temperation is required e.g. processes like PCR
  • these problems are most severe when reaction volumes are less than 5 ⁇ L and larger than 50 ⁇ L.
  • reaction vessels with specific flat or oblong configurations in order to minimize the distance between the central and peripheral parts of the bulk of the reaction mixture.
  • An example of this is to perform the incubation in thin capillaries as described by Wittwer, C.T. et al. (The LightCyclerTM: A Microvolume Multisample Fluorimeter with Rapid Temperature Control, BioTechniques 22: 176- 181, January 1997).
  • One disadvantage with this approach is that the glass capillaries, loosely attached to their plastic holding portions, require extensive manual handling. The choice of glass capillaries makes possible both rapid temperation of the reaction mixture and detection of fluorescence after amplification.
  • a glass capillary tends to maximize the surface-to-fluid contact, with all the consequences this has on mixing and temperation. Further, the use of glass capillaries has the additional draw-back of obstructing the post-PCR processing of the sample. Examples of post-PCR processing include DNA sequencing procedures etc.
  • Other ways to solve the problem with mixing and temperature heterogeneity is to introduce perturbation by agitating or shaking the reaction vessel. Specific instruments designed for this purpose are for example various kinds of flask shakers and so called Vortex machines. A problem often encountered with this approach is that the perturbation periodicity may cause currents or standing waves and therefore incomplete homogeneity.
  • Yet another approach is the use of flow-through systems, where a constantly mowing liquid is subjected to heating.
  • WO 98/49340 discloses a temperature cycling device and method where a reaction mixture and a sample is loaded into loading wells on a disposable rotor, which rotor is then placed into a centrifugal thermal cycling device and spun, so that the reaction mixture and sample are moved by centrifugal force to a reaction well at the periphery of the rotor.
  • the device comprises heating means, for example infrared lights, convection heating elements or microwave sources.
  • provisions for cooling the rotor are included in the specification. According to one embodiment, the rotor speed is increased, resulting in air being drawn into the device and rapidly cooling the contents of the reaction chambers at the periphery of the rotor.
  • a coolant gas can be used in addition to ambient air. Refrigerated air is given as an example of coolant gases.
  • WO 98/49340 implies the use of different speeds of rotation. Further, WO 98/49340 does not address the problems of mixing and homogenous temperation. For example, it does not specify the direction of heating, nor does it contemplate simultaneous heating and cooling.
  • DE 19501 105 A 1 discloses a centrifuge with a temperature control system where a circulating fluid enters the rotor from above and flows out-wards and down-wards in the direction of the radius, around the test-tubes or sample containers. The inventor of the centrifuge according to DE 19501 105 criticises the hitherto known devices using a radiating source of heat and rejects them as unsatisfactory.
  • thermocycling device and corresponding method In particular, the need for a fast and accurate thermocycling device and corresponding method is not yet satisfied by the prior art devices and methods.
  • FIG. 1 shows schematically a first embodiment of the invention, having a device for temperature measurement (7) communicating with a processor (4);
  • Fig. 2 shows a second embodiment of the invention, where the device for temperature measurement (7) is supplemented with a laser source (8) and sensor (9);
  • Fig. 3 shows a third embodiment of the invention, where the temperature is measured by a probe (12), communicating via a transmitter (13) and receiver (14) with the processor (4);
  • Fig. 4 shows a schematic cross section of a device according to the invention, showing basic components, such as the heating mantle (6),
  • Fig. 5 shows a schematic view from above of an embodiment according to Fig. 2;
  • Fig. 6 shows a schematic view from above of an embodiment, e.g. an embodiment according to Fig. 1
  • Fig. 7 shows a schematic cross section of a device with a heat source (17) placed in a lower mantle half (16) which can be moved vertically.
  • the direction of the gravitational field Described with vectors, the direction of the gravitation field is the same as the resulting vector when a vector representing the centrifugal force, that is a vector at right angle to the axis of the centrifuge rotor directed from the centre of the rotor, is added to the vector representing the gravitation of earth. Consequently, downwards is in the present text defined as the same direction as the gravitation field as defined by the summed vectors representing centrifugal force and gravitation.
  • Reaction mixture Any fluid reaction mixture, preferably a liquid reaction mixture, in which the reaction kinetics are influenced by temperature and where a faster, more efficient and homogenous temperation is desired.
  • reactions suitable for the present device and method are chemical / biochemical reactions within the field of high throughput screening and biochemical reactions involving repeated temperation, e.g. cyclic temperature changes, including a polymerase chain reaction (PCR), a ligase chain reaction (LCR). a "gapped-LCR-reaction", a nucleic acid sequence-based amplification (NASBA), a self-sustained replication (3SR). a transcription mediated amplification (TMA), a stand displacement amplification (SDA), a target amplification, a signal amplification, or a combination of any of the above.
  • PCR polymerase chain reaction
  • LCR ligase chain reaction
  • NASBA nucleic acid sequence-based amplification
  • 3SR self-sustained replication
  • TMA transcription mediated
  • a polymerase chain reaction involves the following steps: 1) Preparation of the reaction mixtures, i.e. preparation of the samples to be tested;
  • Amplification i.e. the exponential replication of the DNA molecules
  • Step 2 involves repeated temperature changes to take the reaction mixture through the steps of annealing and extension of the nucleotide strands.
  • Inefficient temperation that is diffuse temperatures in the reaction mixture leads to unspecific amplification products.
  • the necessity of a fast and homogenous temperation of the reaction mixture is central for the quality and reliability of the reaction.
  • Reaction vessel Any vessel capable of containing a reaction mixture within the temperature range necessary for performing the reaction.
  • reaction vessels suitable for use according to the invention include, but are not limited to, the following: test tubes, so called micro tubes, Eppendorf-tubes, a single well or a multitude of wells in a microtitre plate, such as a microtitre plate of the 96-hole format, and various formats with a high density arrays of wells, such as the 192-hole format, the 384-hole format, denser formats or the like.
  • the reaction vessel for use according to the present invention can be a conventional, commercially obtainable reaction vessel as listed above, or a reaction vessel specially adapted for use in the inventive device, for example including an optical element at its distal end, a special colour or surface for absorbing heat at its distal end or having opaque, isolating or reflective surfaces on its side walls etc.
  • the reaction mixture is situated in a reaction vessel, e.g. a vessel having at least one opening and one closed end. substantially in the opposite direction of the open end.
  • Said vessel is loaded with a sample and at least one reactant, which by definition constitute the reaction mixture and which mixture is to be homogeneously incubated.
  • Reactants are dispensed through the open end which after dispensing may be sealed, for example using a lid.
  • Dispensing of reagents may be performed using manual or automated pipetting devices or, in a preferred embodiment of the invention, using predispensed reagent capillaries (PCT/SE91/00343) or reagent cartridges (PCT/SE97/01562).
  • the closed end is defined as the distal end pointing in the same direction as the current gravitation field.
  • the open end or the end closed with a lid or reagent cartridge, is called the proximal end.
  • FIG. 1 A device according to the present invention is shown in figure 1 comprising means, such as a rotor 1 for holding at least one reaction vessel 2 with contents; means for subjecting the said at least one reaction vessel and its contents to a centrifugal force, such as a motor 3; means 5 and
  • a temperature sensor for heating the part of the reaction vessel directed outwards in relation to the centrifugal force; and means for cooling the proximal end of the reaction vessel (not shown).
  • the temperature sensor 7 is shown, with a line indicating schematically, that the reading is taken from the sample containing end of a rotating reaction vessel 2.
  • the temperature sensor 7 is preferably an IR sensor.
  • a processor 4 is shown.
  • This processor can be any conventional logic circuit loaded with operating instructions in the form of computer code, or a circuit specially adapted for the inventive device.
  • the functions of the processor include at least the following: to process the temperature signal from the temperature sensor 7 and to control the operation of the motor 3 and the heating / cooling source 5 according to one or more programmes, chosen by the operator.
  • said means 1 for holding at least one reaction vessel is a rotor, e.g. a rotor chosen among the following: a drum rotor, a swing-bucket rotor and a fixed angle rotor.
  • the chosen rotor is preferably modified to allow unhindered thermal contact between the distal or "lower" end of the reaction vessels and the heating source.
  • the rotor may suitably modified to allow efficient cooling of the proximal end.
  • the heating source 5 and 6 can be any heating source, capable of heating the distal ends of the reaction vessels, e.g. a radiating source, such as a heating element with electric resistance wires, an IR-source, a microwave element and the like.
  • a radiating source such as a heating element with electric resistance wires, an IR-source, a microwave element and the like.
  • the heating and cooling is effected through the use of at least one external source of heat and cold (illustrated throughout the figures as 5) connected to a mantle 6.
  • the mantle embraces the rotational path of the reaction vessels 2 during at least part of this path as indicated in the cross sections of figures 1, 2, 3 and 4.
  • the mantle 6 is adapted to the shape of the rotor, as schematically indicated in Fig. 5 and 6, showing two embodiments of the invention.
  • Fig. 7 an embodiment is shown, where the mantle or a part thereof is movable in relation to the rotational path of the reaction vessels.
  • the movable part of the mantle is then preferably a circular or partially circular reflector 16 containing a source of heat 17 and arranged so that it can be moved closer to and away from the rotational part of the reaction vessels.
  • the heating source may also be situated inside the rotor, at the distal or lower ends of the reaction vessels (not shown).
  • a telecentric lens is positioned between the heating source and the reaction vessel or reaction vessels.
  • the cooling source or means for cooling can be chosen among convection cooling and a circulating cooling medium, e.g. a refrigerated gas, such as air and preferably nitrogen.
  • a circulating cooling medium e.g. a refrigerated gas, such as air and preferably nitrogen.
  • the cooling medium is let into the mantle and thus comes in contact with the rotating reaction vessels.
  • the environment of the rotor is refrigerated with exception of the mantle. By moving the mantle in relation to the rotor, e.g. raising or lowering it into close proximity of the rotating reaction vessels, said vessels are heated. By lowering, raising or otherwise removing the mantle, the surrounding cold environment is again allowed to contact the rotating reaction vessels.
  • the reaction vessels 2 can be any one of the following: a set of individual tubes, e.g. Eppendorf-tubes. individual wells on a microtitre plate or individual test tubes.
  • Fig. 2 shows schematically an embodiment where a radiation source 8 emits radiation, e.g. a laser beam which intersects the rotational path of the reaction vessels.
  • the reflectance of this radiation is detected by a sensor 9.
  • the temperature sensor 7, e.g. an IR sensor, may communicate with the reflectance sensor 9 via a processor 10, e.g. for the purpose of adjusting the temperature measurements to the rotational speed.
  • the radiation source 8 and the reflectance sensor 9 may also be used for detecting chemical reactions in the samples, e.g. the light reflectance or emission indicating the end point of a reaction or a positive or negative test answer.
  • a user interface 1 1 is indicated.
  • Said user interface can include a key board or similar for inputting the selection of operating parameters or choice of pre-programmed operating schemes, a display for showing the progress of the operation, process parameters etc.
  • the device includes means for reading information regarding sample identity, operating instructions etc.
  • information regarding sample identity, operating instructions etc includes operating parameters, such as time and temperature, number of cycles, post-PCR temperature etc., sample information, such as date, source, patient identity, quality etc., and reagent information, such as batch number, date, reagent quantity, type etc.
  • the samples or reaction vessels carry the above or similar information, e.g. in the form of optically readable signs, such as bar codes, optically readable discs etc, or electronically readable information, such as information contained on a magnetic carrier or on an integrated circuit or chip.
  • optically readable signs such as bar codes, optically readable discs etc
  • electronically readable information such as information contained on a magnetic carrier or on an integrated circuit or chip.
  • the samples are identified and the operation performed according to information contained in each sample carrier, e.g. each microtitre plate.
  • the information can be read by the operator, e.g. using a barcode reader, or by the device, automatically detecting the information when the samples are loaded into the device.
  • Fig. 3 is shown an embodiment, where temperature reading and control is effected via a sensor 12 placed in one of the reaction vessels, communicating with the processor 4 via a transmitter 13 and receiver 14.
  • the sensor is e.g. a thermocouple and the transmitter / receiver system can be a system utilising IR signals.
  • Fig. 4 shows a schematic cross section of a device according to the invention, where the mantle 6 is shown.
  • the reaction vessels 2, the rotor 1 and the motor 3 are as disclosed above.
  • Fig. 5 shows a schematic view from above, e.g. of an embodiment according to fig. 2.
  • the mantle 6 having an inlet and an outlet, indicated by arrows, leading into and out from the mantle, respectively. It is seen, that the mantle covers only part of the rotational path of the reaction vessels 2, leaving a sector for unhindered measurement.
  • the measurement is shown including the IR sensor 7, a laser source 8 and a reflectance sensor 9.
  • Fig. 6 an embodiment is shown, where the mantle 6 surrounds the entire rotational path of the reaction vessels 2.
  • the measurements, here indicated by the sensor 7, are taken through the mantel, preferably through a section 15 of the mantle, being permeable to or able to transmit the signals detected by the sensor.
  • Fig. 7 shows a schematic cross section of an embodiment where the heating source 17, e.g. a tubular IR lamp, is arranged in a movable reflector 16.
  • the heating source 17 e.g. a tubular IR lamp
  • the sample volumes are efficiently heated.
  • the lamps are deactivated and the reflector lowered, the heat dissipates quickly from said sample volumes.
  • the cooling can be aided by refrigerating the entire inner volume of the device or the volume closes to the rotating reaction vessels.
  • the reflector 16 need not be arranged below the rotational path of the reaction vessels, but can also be arranged above or around said path. In those cases, the reflector is moved downwards or inwards until it comes in close proximity of the rotating reaction vessels.
  • said device is capable of subjecting the contents of the reaction vessel or vessels to significant centrifugal force, preferably a centrifugal force in the interval of about 500 x g to about 20.000 x g or higher, preferably in the interval of about 1.500 x g to about 20.000 x g, and most preferably about 5.000 x g to about 15.000 x g.
  • the temperation achieved by the present inventive device or method is naturally a function of the reaction volume, its constitution, the temperature and the centrifugal force.
  • a device according to one embodiment of the invention comprises means for cooling the part of the reaction vessel directed inwards in relation to the centrifugal force.
  • the rotor is modified to allow unhindered thermal contact between the proximal or "upper" end of the reaction vessels and the cooling medium.
  • the means for heating comprise at least one source of heat, for instance a radiation source emitting radiation within a wavelength range generating heat, e.g. an IR source, an electric element, hot gas or hot liquid, which is positioned within or connected to a centrifuge in such way that the heat when emitted, reach the distal end or ends, of one or several reaction vessels when these reaction vessels, being appropriately situated in the rotor of the centrifuge, are centrifuged.
  • this source of heat can be switched on and off without terminating the centrifugation.
  • the effect of the heat source should be high enough to bring the complete amount of reaction mixture contained in the reaction vessel or reaction vessels, to the temperature being appropriate for the desired chemical reaction.
  • the heating means can preferably comprise a temperature sensor or sensors or a thermostat for monitoring and controlling the heating.
  • hot air is forced into a space surrounding the rotating reaction vessels or at least the apices of said vessels. This space is referred to as a "heating mantle”.
  • the hot air referred to in this context is air or a suitable gas mixture, heated to a temperature which exceeds the melting temperature of the material of the reaction vessels, e.g. the thermoplastic of the Eppendorf-tubes or microtitre wells.
  • the temperature is preferably as high as possible, given the restrictions posed by the equipment used, and preferably a temperature in the interval of 200 to 800 degrees Celsius, most preferably about 600 degrees Celsius.
  • the heating mantle is removed from the immediate vicinity of the reaction vessels, either by moving the heating mantle in relation to the rotor, e.g. by raising the heating mantle, or by lowering the rotor.
  • the rapidly rotating reaction vessels will then come in contact with surrounding air or gas mixture, e.g. the air inside the centrifuge or air aspirated from the surrounding room.
  • the air or gas mixture inside the centrifuge is cooled to a temperature below the ambient temperature.
  • the rotor can also be enclosed in a larger space, which is refrigerated. When the heating mantle is moved away from immediate contact with the reaction vessels, the refrigerated air will rapidly cool the vessels.
  • the means for cooling can comprise means for leading a cooling medium, e.g. a gas, liquid or ambient air into close proximity of the proximal or "upper" end of the reaction vessels.
  • a cooling medium e.g. a gas, liquid or ambient air
  • a suitable cooling medium is liquid nitrogen or refrigerated nitrogen gas.
  • reaction vessels including the complete reaction mixture or a subset of this, are placed in the rotor of the centrifuge with the closed end directed downwards or otherwise according to standard practice for centrifuging the reaction vessels in question.
  • the centrifuge is then started, that is, the engine which brings the rotor to spin is switched on.
  • the rotation is kept at constant speed.
  • the heating source is now switched on leading to increased temperature predominantly at the apices of the reaction vessels.
  • the heat will be transferred through the material of the walls of the reaction vessels, to the most distal part of the bulk of the reaction mixture. Increased molecular motion due to increased temperature will expand, that is, decrease the density of this heated part of the reaction mixture.
  • the means for cooling acting simultaneously on the upper or proximal part of the reaction vessel will cooperate to ensure thorough mixing and homogenization. This chain of events will carry on, eventually leading to a thoroughly mixed, homogenous reaction mixture and a homogeneous temperature distribution in the bulk of the reaction mixture.
  • the device according to the invention is equipped with an IR-sensor, and preferably a focussed IR-sensor monitoring the temperature of the contents in the rotating vessels.
  • IR-sensor preferably a focussed IR-sensor monitoring the temperature of the contents in the rotating vessels.
  • Prior art methods of temperature control often use a thermocouple, placed in one reaction vessel, partaking in the thermocycling procedure. This is however not necessarily accurate. As most plastic materials, used for reaction vessels, do not absorb IR radiation, the measurement according to the present invention will actually give the temperature in the sample itself. The measurement can be governed by an algorithm, giving not only the mean temperature of the rotating vessels but also possible deviations from this mean value.
  • the above IR-sensor is preferably equipped with a laser, emitting a concentrated ray of light hitting the reaction vessels.
  • This laser "point" visible on the vessels can be registered by an optional sensor and used for controlling the focus of the IR sensor, the speed of rotation, for triggering the measurement of sample temperature and for refiectometric and/or fluorometirc measurements.
  • a higher accuracy can be reached.
  • the IR-source should be chosen so as to emit IR radiation at a wavelength clearly different from the reading wavelength of the IR-sensor.
  • the simultaneous cooling from the opposite direction of the gravitation field provided according to one embodiment of the invention, efficiently increases the degree of density homogenisation, that is, shortens the time for temperation and homogenisation of the reaction mixture.
  • a method according to the invention comprises the following steps: i) at least one reactant is measured into a reaction vessel, ii) said reaction vessel with contents is placed in a device capable of subjecting it simultaneously to centrifugation and heating; and iii) said reaction vessel is subjected to centrifugation iv) the distal end of the reaction vessel is subjected to heating.
  • At least one reactant is added using a capillary or similar device, which only releases its content upon centrifugation.
  • a method comprises the following steps: i) at least one reactant is measured into a reaction vessel, said vessel carrying information regarding the intended treatment or process steps, ii) the information is read by a device, part of or connected to a device capable of subjecting it simultaneously to centrifugation and heating iii) said reaction vessel with contents is placed in the above device for centrifugation and heating; and iv) said reaction vessel is subjected to centrifugation v) the distal end of the reaction vessel is subjected to heating;
  • steps iv and v being performed according to the information contained on the reaction vessel.
  • the risk of operator error is minimized if not entirely removed.
  • the method also allows a large extent of automation of the process and further, it simplifies the compliance with quality control schemes.
  • the present invention also discloses a new method for performing chemical reactions in fluid media contained in reaction vessels, characterized in that a device according to any one of attached apparatus claims is used.
  • the present invention discloses a novel and efficient method for performing reactions demanding a high degree of homogenisation and involving repeated temperation e.g. analyses and synthesis involving themocycling.
  • analyses and synthesis involving themocycling e.g. analyses and synthesis involving themocycling.
  • One example of such analyses is the polymerase chain reaction (PCR) technique.
  • PCR polymerase chain reaction
  • Another important application is in the field of high throughput screening. This and other methods are outlined previously in the description.
  • the device according to the invention is particularly suitable for a variation of the PCR analysis, generally known as "hot start PCR".
  • the temperature is first set to a temperature above the annealing temperature of the primers.
  • the rotor is rotated on a lower speed, sufficient to assist in temperation.
  • the reagents are added with the aid of reagent capillaries or reagent cartridges (e.g. capillaries or cartridges as disclosed in PCT/SE91/00343 and PCT/SE97/01562 by same applicant).
  • the emptying of the reagent capillaries or cartridges is triggered by increasing the speed of rotation. At a higher rotational speed, the capillaries or cartridges are emptied by the centrifugal force and the PCR analysis can be carried on, as described above in the description.

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Abstract

La présente invention concerne un procédé permettant de réaliser avec efficacité l'homogénéisation d'un échantillon qui est soumis à centrifugation en même temps qu'à un réchauffage et éventuellement aussi à un refroidissement. A cet effet, on utilise un dispositif comportant au moins un rotor (1) servant de support aux cuves de réaction (2), un moteur (3) relié au rotor, des organes tels qu'un processeur (4) pour réguler la vitesse du rotor, et des organes (5, 6) permettant de réchauffer et refroidir le contenu des cuves de réaction. De fait, les réchauffeurs (6) recouvrent au moins les sommets des cuves de réaction sur au moins une partie du chemin de rotation de ces cuves. En outre, les réchauffeurs opèrent à une température largement supérieure à la température de fusion des cuves de réaction. L'invention concerne également un procédé permettant de mener des réactions chimiques, et plus particulièrement de mener des réactions biochimiques impliquant un thermocyclage, notamment des réactions d'amplification en chaîne par polymérase.
PCT/SE2000/000586 1999-03-25 2000-03-24 Homogeneisation de petits volumes de melanges de reactions chimiques par centrifugation et chauffage WO2000058013A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
DE60044429T DE60044429D1 (de) 1999-03-25 2000-03-24 Homogenisierung von kleinvolumigen mischungen durch zentrifugierung und erhitzen
AT00921255T ATE468175T1 (de) 1999-03-25 2000-03-24 Homogenisierung von kleinvolumigen mischungen durch zentrifugierung und erhitzen
AU41591/00A AU766869B2 (en) 1999-03-25 2000-03-24 Homogenising of small-volume mixtures by centrifugation and heating
JP2000607757A JP4681736B2 (ja) 1999-03-25 2000-03-24 遠心力および加熱による小体積混合物の均一化
US09/937,383 US6783993B1 (en) 1999-03-25 2000-03-24 Homogenizing of small-volume mixtures by centrifugation and heating
CA002366732A CA2366732C (fr) 1999-03-25 2000-03-24 Homogeneisation de petits volumes de melanges de reactions chimiques par centrifugation et chauffage
HK02105260.0A HK1043749B (en) 1999-03-25 2000-03-24 Homogenising of small-volume mixtures by centrifugation and heating
EP00921255A EP1173284B1 (fr) 1999-03-25 2000-03-24 Homogeneisation de petits volumes de melanges de reactions chimiques par centrifugation et chauffage

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE9901104-1 1999-03-25
SE9901104A SE9901104D0 (sv) 1999-03-25 1999-03-25 Device and method for performing chemical reactions involving thermocykling
SE9902378-0 1999-06-22
SE9902378A SE9902378D0 (sv) 1999-06-22 1999-06-22 Device and method for homogenising small-volume chemical reaction mixtures

Publications (1)

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WO2000058013A1 true WO2000058013A1 (fr) 2000-10-05

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US (1) US6783993B1 (fr)
EP (1) EP1173284B1 (fr)
JP (1) JP4681736B2 (fr)
CN (1) CN1125687C (fr)
AT (1) ATE468175T1 (fr)
AU (1) AU766869B2 (fr)
CA (1) CA2366732C (fr)
DE (1) DE60044429D1 (fr)
ES (1) ES2346128T3 (fr)
RU (1) RU2266163C2 (fr)
WO (1) WO2000058013A1 (fr)

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WO2003000428A1 (fr) * 2001-06-21 2003-01-03 Alphahelix Ab Dispositif de thermocyclage et systeme de rotor correspondant
WO2002060584A3 (fr) * 2001-01-29 2003-02-13 Genset Sa Procede de mise en oeuvre d'un protocole biochimique en flux continu dans un microreacteur
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WO2005105282A1 (fr) 2004-04-30 2005-11-10 Mats Malmqvist Systeme de cuve de reaction ferme
DE102004058247A1 (de) * 2004-12-02 2006-06-08 Kendro Laboratory Products Gmbh Luftgekühlte Zentrifuge
EP1567861A4 (fr) * 2002-11-20 2008-04-09 Corbett Life Science Pty Ltd Dispositif centrifuge et procede permettant d'effectuer des analyses par liaison
AU2003227117B2 (en) * 2002-05-01 2009-01-15 Corbett Life Science Pty Ltd Device for the amplification of DNA, comprising a microwave energy source
AU2003283064B2 (en) * 2002-11-20 2009-06-04 Qiagen Gmbh Centrifugal device and method for performing binding assays
EP2107125A1 (fr) * 2008-03-31 2009-10-07 Eppendorf Array Technologies SA (EAT) PCR en temps réel de cibles sur un micro-réseau
US7628961B2 (en) * 2001-09-15 2009-12-08 Ahram Biosystems, Inc. Method and apparatus for amplification of nucleic acid sequences by using thermal convection
WO2011042426A1 (fr) 2009-10-05 2011-04-14 Alphahelix Molecular Diagnostics Ab (Publ) Rotor multifonctionnel
WO2012037978A1 (fr) 2010-09-24 2012-03-29 Alphahelix Molecular Diagnostics Ab Nouveaux dispositif et procédé pour la mise en oeuvre d'une pcr quantitative directe en temps réel
WO2014126545A1 (fr) * 2013-02-18 2014-08-21 Akman Serhan Centrifugeuse structurée pour être utilisée dans la préparation de fibrine riche en plaquettes
US9346055B2 (en) 2001-10-30 2016-05-24 Ahram Biosystems, Inc. Method and apparatus for amplification of nucleic acid sequences using immobilized DNA polymerase
US9573133B2 (en) 2010-01-12 2017-02-21 Ahram Biosystems, Inc. Two-stage thermal convection apparatus and uses thereof
US9573134B2 (en) 2010-01-12 2017-02-21 Ahram Biosystems, Inc. Three-stage thermal convection apparatus and uses thereof
US11279967B2 (en) 2013-03-14 2022-03-22 Gen-Probe Incorporated System and method for conducting an assay
EP4434636A1 (fr) * 2023-03-23 2024-09-25 Sigma Laborzentrifugen GmbH Ensemble de produit de fermentation de centrifugeuse de laboratoire, produit de fermentation de mesure et centrifugeuse de laboratoire

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JP5381100B2 (ja) * 2007-02-22 2014-01-08 東洋紡株式会社 核酸増幅装置
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KR101119955B1 (ko) * 2009-05-11 2012-03-15 주식회사 메디사랑 피브리노겐을 생성하는데 사용되는 항온원심분리기
EP2737294B1 (fr) 2011-07-27 2024-06-26 Curetis GmbH Appareil et procédé de lyse d'un échantillon, en particulier pour la lyse automatisée et / ou régulée d'un échantillon
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FR3000549B1 (fr) * 2012-12-27 2015-04-24 Centre Nat Rech Scient Procede et dispositif pour caracteriser un milieu fluide a l'aide d'un substrat semi-conducteur
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Cited By (39)

* Cited by examiner, † Cited by third party
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EP1110614A3 (fr) * 1999-12-24 2002-02-27 Astrium GmbH Dispositif pour tempérer des récipients
WO2002060584A3 (fr) * 2001-01-29 2003-02-13 Genset Sa Procede de mise en oeuvre d'un protocole biochimique en flux continu dans un microreacteur
WO2003000428A1 (fr) * 2001-06-21 2003-01-03 Alphahelix Ab Dispositif de thermocyclage et systeme de rotor correspondant
CN101003825B (zh) * 2001-09-15 2012-08-22 阿赫姆生物系统公司 应用热对流进行核酸序列扩增的方法和装置
US20120021463A1 (en) * 2001-09-15 2012-01-26 Ahram Biosystems, Inc. Method and apparatus for amplification of nucleic acid sequences by using thermal convection
US9765376B2 (en) * 2001-09-15 2017-09-19 Ahram Biosystems, Inc. Method and apparatus for amplification of nucleic acid sequences by using thermal convection
US8053215B2 (en) 2001-09-15 2011-11-08 Ahram Biosystems, Inc. Method and apparatus for amplification of nucleic acid sequences by using thermal convection
US20140170707A1 (en) * 2001-09-15 2014-06-19 Ahram Biosystems, Inc. Method and apparatus for amplification of nucleic acid sequences by using thermal convection
US7628961B2 (en) * 2001-09-15 2009-12-08 Ahram Biosystems, Inc. Method and apparatus for amplification of nucleic acid sequences by using thermal convection
US9346055B2 (en) 2001-10-30 2016-05-24 Ahram Biosystems, Inc. Method and apparatus for amplification of nucleic acid sequences using immobilized DNA polymerase
AU2003227117B2 (en) * 2002-05-01 2009-01-15 Corbett Life Science Pty Ltd Device for the amplification of DNA, comprising a microwave energy source
WO2004045771A1 (fr) * 2002-11-19 2004-06-03 Alphahelix Ab Procede et dispositif d'homogeneisation rapide et de transport de masse
US7371205B2 (en) 2002-11-19 2008-05-13 Alphahelix Molecular Diagnostics Ab Device for asymmetric heating and cooling of reaction mixtures during centrifuging and rotor means therefore
WO2004045774A1 (fr) * 2002-11-19 2004-06-03 Alphahelix Ab Dispositif et moyens rotor pour un tel dispositif
AU2003283064B2 (en) * 2002-11-20 2009-06-04 Qiagen Gmbh Centrifugal device and method for performing binding assays
EP1567861A4 (fr) * 2002-11-20 2008-04-09 Corbett Life Science Pty Ltd Dispositif centrifuge et procede permettant d'effectuer des analyses par liaison
WO2005105282A1 (fr) 2004-04-30 2005-11-10 Mats Malmqvist Systeme de cuve de reaction ferme
DE102004058247B4 (de) * 2004-12-02 2013-03-14 Thermo Electron Led Gmbh Luftgekühlte Zentrifuge
DE102004058247A1 (de) * 2004-12-02 2006-06-08 Kendro Laboratory Products Gmbh Luftgekühlte Zentrifuge
EP2107125A1 (fr) * 2008-03-31 2009-10-07 Eppendorf Array Technologies SA (EAT) PCR en temps réel de cibles sur un micro-réseau
WO2011042426A1 (fr) 2009-10-05 2011-04-14 Alphahelix Molecular Diagnostics Ab (Publ) Rotor multifonctionnel
US9573133B2 (en) 2010-01-12 2017-02-21 Ahram Biosystems, Inc. Two-stage thermal convection apparatus and uses thereof
US9573134B2 (en) 2010-01-12 2017-02-21 Ahram Biosystems, Inc. Three-stage thermal convection apparatus and uses thereof
US10086375B2 (en) 2010-01-12 2018-10-02 Ahram Biosystems, Inc. Two-stage thermal convection apparatus and uses thereof
US10086374B2 (en) 2010-01-12 2018-10-02 Ahram Biosystems, Inc. Three-stage thermal convection apparatus and uses thereof
WO2012037978A1 (fr) 2010-09-24 2012-03-29 Alphahelix Molecular Diagnostics Ab Nouveaux dispositif et procédé pour la mise en oeuvre d'une pcr quantitative directe en temps réel
US9273351B2 (en) 2010-09-24 2016-03-01 Alphahelix Molecular Diagnostics Ab Device and method for conducting direct quantitative real time PCR
WO2014126545A1 (fr) * 2013-02-18 2014-08-21 Akman Serhan Centrifugeuse structurée pour être utilisée dans la préparation de fibrine riche en plaquettes
US11279967B2 (en) 2013-03-14 2022-03-22 Gen-Probe Incorporated System and method for conducting an assay
US11434521B2 (en) 2013-03-14 2022-09-06 Gen-Probe Incorporated Method for conducting an assay
US11732288B2 (en) 2013-03-14 2023-08-22 Gen-Probe Incorporated Assembly having reagent pack loading station
US11732289B2 (en) 2013-03-14 2023-08-22 Gen-Probe Incorporated Receptacle distribution system
US11761026B2 (en) 2013-03-14 2023-09-19 Gen-Probe Incorporated Diagnostic system and method
US11761027B2 (en) 2013-03-14 2023-09-19 Gen-Probe Incorporated System and method for receiving and storing reagent packs in an instrument
US11834701B2 (en) 2013-03-14 2023-12-05 Gen-Probe Incorporated Reagent pack changer
US12110535B2 (en) 2013-03-14 2024-10-08 Gen-Probe Incorporated Method for reconstituting a reagent
US12173352B2 (en) 2013-03-14 2024-12-24 Gen-Probe Incorporated Method for receiving and storing reagent packs in an instrument
EP4434636A1 (fr) * 2023-03-23 2024-09-25 Sigma Laborzentrifugen GmbH Ensemble de produit de fermentation de centrifugeuse de laboratoire, produit de fermentation de mesure et centrifugeuse de laboratoire
WO2024194313A1 (fr) 2023-03-23 2024-09-26 Sigma Laborzentrifugen Gmbh Utilisation d'un produit factice de mesure

Also Published As

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RU2266163C2 (ru) 2005-12-20
ES2346128T3 (es) 2010-10-11
EP1173284B1 (fr) 2010-05-19
EP1173284A1 (fr) 2002-01-23
AU4159100A (en) 2000-10-16
JP2002539937A (ja) 2002-11-26
CN1352576A (zh) 2002-06-05
AU766869B2 (en) 2003-10-23
CN1125687C (zh) 2003-10-29
CA2366732A1 (fr) 2000-10-05
DE60044429D1 (de) 2010-07-01
RU2001128879A (ru) 2003-07-27
CA2366732C (fr) 2008-11-18
JP4681736B2 (ja) 2011-05-11
ATE468175T1 (de) 2010-06-15
HK1043749A1 (en) 2002-09-27
US6783993B1 (en) 2004-08-31

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